The mechanism which coordinates the replication and the segregation of the genetic material with cellular division is one of the most fundamental examples of a system of metabolic regulation. This laboratory is investigating the structure and the control of the replication of extrachromosomal genetic elements in bacteria (plasmids) not only because an understanding of DNA replication and its control in bacteria will be an important advance in its own right, but also because this system can be considered to be a prototype of the more complex chromosomal systems of eucaryotes. Most of our research is on the drug resistance plasmids (R plasmids) of the Enterobacteriaceae because of their importance to the health sciences and because of the remarkable mechanisms which R plasmids have evolved to confer multiple drug resistance to host cells. There are four major areas of investigation. The first area is physical mapping studies on R plasmid DNA and the isolation of R plasmid mutants which affect important plasmid genes and functional sites. The second is the regulation of R plasmid replication, especially with regard to the reversible amplification of the r-determinants component which harbors most of the R plasmid drug resistance genes. The third is the structure of R plasmids in both the non-replicating and replicating states. The fourth is the mechanism of segregation of plasmid DNA at cellular division and the localization and internal organization of plasmid DNA within bacterial cells. This research will contribute in a fundamental way to our understanding of the structure, function, and replication of R plasmids which are the major cause of multiple drug resistance in pathogenic bacteria. The information obtained in this comparatively simple procaryotic system will also be useful in the formulation of more precise questions on the molecular and genetic events which regulate chromosome reproduction and mitosis in eucaryotes.